This invention relates to 5-(alkylidene-cycloalkyl)-pyrazoles and 5-(alkylidene-heterocyclyl)-pyrazoles, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock.
Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors are limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of sulfonylbenzene compounds which inhibit COX have been described in patent publications (WO 97/11704, WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, EP 554829 and EP 1099695). U.S. Non-provisional application Ser. No. 09/798,752, filed Mar. 2, 2001 (which claims priority to U.S. Provisional application No. 60/186,869 filed Mar. 3, 2001) refers to certain sulfonylpyrazole COX-2 inhibitors.
Filed simultaneously with the present application on Nov. 2, 2001, are U.S. Provisional Applications entitled “Hydrazinyl and Nitrogen Oxide Pyrazoles”; “Heterocyclo-Alkylsulfonyl Pyrazoles”; “5-Heteroatom-Substituted Pyrazoles”; and “5-Heterocyclo-Pyrazoles”, which refer to certain pyrazole COX-2 inhibitors. The aforesaid applications are herein incorporated in their entireties by reference.